Antagonists to both estrogen and androgen receptors have been developed for the treatment of hormone-related conditions. For example, antiestrogenic agents are useful for the treatment of breast cancer and antiandrogenic agents are useful for the treatment of prostate cancer.
Breast cancer, at 182,000 cases per year, is the most common cancer diagnosis among women in the United States, accounting for over 40,000 deaths annually (Greenlee, 2000). It is estimated that one in eight women will develop breast cancer during their lifetime and one in three of those will die from the disease. Of those women diagnosed with breast cancer, approximately 60% have tumors that are classified as hormone-responsive, meaning that the tissue contains elevated levels of the estrogen receptor and the tumor cell proliferation is stimulated by circulating estrogens (Scott, 1991). Various available treatments include surgery (e.g., lumpectomy, mastectomy or modified radical mastectomy, which removes the breast and underlying muscle along with adjacent lymph nodes), radiation, chemotherapy or biological treatments.
Hormonal therapy characterized as either removal of estrogen producing tissues, inhibition of estrogen biosynthesis or blockade of estrogen receptors by antagonists (e.g., tamoxifen (Nolvadex®) and Faslodex®, raloxifene, and idoxifene), has been shown to produce a positive objective response (Beatson, 1896; Boyd 1900; Bhatanagar, 1999; Cole, 1971; and Lancet 351, 1998). Such interventions, however, are often accompanied by major side effects that are tolerated because of the particular risks associated with the primary disease. Over the past 10 years, studies with antiestrogens structurally related to tamoxifen have demonstrated that some of the side effects can be ameliorated, depending upon the features incorporated within the structure of the drug. Agents that may block cancer cell proliferation (antagonism) without eliminating the beneficial effects on bone density and cardioprotection have been termed Selective Estrogen Receptor Modulators (SERMs) (Grese; Levenson, 1999). Known non-steroidal antagonists that are tamoxifen-like and raloxifen-like display antiestrogen effects in some tissues and estrogen-like effects in others. These SERMs may be beneficial for the treatment of hormone responsive cancers (or potentially as prophylactic agents) without causing osteoporosis or increasing the risk for cardiovascular disease. However, their receptor affinity is generally less than that of estradiol, and because they have a non-steroidal structure, they often exhibit additional, non-hormonal effects. Additionally, hormone responsive cancers progress to a stage where they become hormone-independent, requiring a subsequent, more aggressive approach.
Prostate cancer is the most common cancer diagnosis among American men (29%) and the second leading cause of death due to cancer (13%) (Landis, 1999; Haas, 1997; Mettlin, 1997). Like breast cancer in women, most of the newly diagnosed cases are hormone responsive and patients experience a reduction in tumor growth or regression with antihormone (antiandrogen) therapy (Roach, 1999).
Hormonal therapy is often used in all phases of prostate cancer treatment to help block production or action of the male hormones that have been shown to fuel prostate cancer. Antiandrogens are divided into two groups: steroidal and non-steroidal. Among widely used approved hormone blockers, often used in combination, are Casodex (bicalutamide), Eulexin (flutamide), Anandron (nilutamide), LG 120907, which are nonsteroidal (see FIG. 9), and Lupron (leuprolide acetate), and Zoladex (goserelin acetate implant), which are peptides that block GnRH release. The nonsteroidal antiandrogens can be displaced by endogenous ligands, i.e., dihydrotestosterone. Therefore, these antiandrogens have not been as successful in the treatment of prostate cancer due to their reversability in binding to the androgen receptor. Some studies have suggested that dihydrotestosterone bromoacetate (DHT-BA) binds irreversibly to the androgen receptor (AR). However, other studies show that DHT-BA apparently binds to aldehyde dehydrogenase and not to the AR (McCammon, 1993). Therefore, DHT-BA is not as optimal in the treatment of prostate cancer.
Because the testicles produce male hormones, some men also undergo testicle removal to cut off the hormone supply. Advanced prostate cancer patients are usually treated with any number of chemotherapeutic drugs such as Novantrone (mitoxantrone), which do not cure the disease but often do ease pain and other symptoms. However, within one to three years of such therapy, there is often recurrence of disease in which the tumor has acquired hormone independence (Galbraith, 1997). At this point, antiandrogen therapy becomes much less effective and a more aggressive intervention is required (Ornstein, 1999). A second issue is that current antiandrogen therapy, even when effective, elicits a number of side effects (e.g., impotence, incontinence, loss of libido, gynecomastia, heat intolerance, or hot flashes) that compromise the patient's quality of life.
Therefore, the development of more therapeutically effective antiestrogenic and antiandrogenic agents that target hormone-dependent tumors would: (1) provide a substantial benefit for the initial reduction of disease, (2) provide a prolonged disease-free interval, (3) improve the long term prognosis, and (4) reduce the incidence and severity of the side effects.